Mycobacterium tuberculosis possesses unique cellular envelope components that contribute to bacterial escape from host immune surveillance.Phosphatidylinositol mannosides(PIMs)and their higher derivatives are importan...Mycobacterium tuberculosis possesses unique cellular envelope components that contribute to bacterial escape from host immune surveillance.Phosphatidylinositol mannosides(PIMs)and their higher derivatives are important molecules implicated in host-pathogen interactions in the course of tuberculosis.However,the biosynthetic regulation of these specific lipids and its effect on the bacterial fate in the infected host remain unclear.Here,we show that a hypothetical M.tuberculosis transcriptional factor designated as MpbR negatively regulates two transporter genes and affects mycobacterial PIM biosynthesis and biofilm formation.MpbR inhibits the accumulation of acylated PIM lipids and triggers the mycobacterium to reduce the production of reactive oxygen species and NO during infection,which enhances the survival of M.tuberculosis in macrophages.MpbR deletion reduces M.tuberculosis lung burdens and inflammation of infected mice.These findings provide new insights into the regulation of mycobacterial lipid metabolism and its correlation with pathogenesis of M.tuberculosis.展开更多
基金supported by the National Key R&D Program of China(2017YFD0500300)the National Natural Science Foundation of China(31730005,31670075 and 31870036)the Ba-Gui Scholar Program of Guangxi(to Z.G.H.).
文摘Mycobacterium tuberculosis possesses unique cellular envelope components that contribute to bacterial escape from host immune surveillance.Phosphatidylinositol mannosides(PIMs)and their higher derivatives are important molecules implicated in host-pathogen interactions in the course of tuberculosis.However,the biosynthetic regulation of these specific lipids and its effect on the bacterial fate in the infected host remain unclear.Here,we show that a hypothetical M.tuberculosis transcriptional factor designated as MpbR negatively regulates two transporter genes and affects mycobacterial PIM biosynthesis and biofilm formation.MpbR inhibits the accumulation of acylated PIM lipids and triggers the mycobacterium to reduce the production of reactive oxygen species and NO during infection,which enhances the survival of M.tuberculosis in macrophages.MpbR deletion reduces M.tuberculosis lung burdens and inflammation of infected mice.These findings provide new insights into the regulation of mycobacterial lipid metabolism and its correlation with pathogenesis of M.tuberculosis.
文摘目的探讨过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptorγ,PPARγ)/CD36通路在结核分枝杆菌(Mycobacterium tuberculosis,Mtb)感染巨噬细胞脂质代谢中的作用。方法以THP-1源性巨噬细胞建立感染模型,将实验分为对照组、Mtb组、Mtb+罗格列酮(rosiglitazone,ROZ)组和Mtb+GW9662组。分别采用Western blot和RT-PCR检测巨噬细胞中PPARγ蛋白和基因表达水平;油红O染色法检测细胞内脂质情况;全自动生化分析仪检测细胞培养上清中总胆固醇(total cholesterol,TC)、甘油三酯(triglycerides,TG)、低密度脂蛋白(low density lipoprotein,LDL-C)和高密度脂蛋白(high density lipoprotein,HDL-C)浓度;免疫组织化学法检测细胞中CD36表达;CCK-8检测巨噬细胞增殖率。结果Mtb感染显著升高巨噬细胞中PPARγ表达(P<0.001)、促进细胞内脂质聚集及CD36表达,降低细胞培养上清中TC、TG、LDL-C和HDL-C含量(P<0.001)和细胞增殖率(P<0.001)。PPARγ激动剂ROZ可显著增强Mtb感染所致的细胞内脂质聚集及CD36表达、进一步下调细胞培养上清中脂质水平及各细胞增殖率,而PPARγ拮抗剂GW9662则逆转上述作用。结论PPARγ通过影响CD36表达在Mtb感染巨噬细胞脂质代谢中发挥一定作用。
